20-[omega-(tertiary-amino) lower alkanoylamido] pregn-5-en-3beta-ols, esters corresponding, and intermediates thereto



United States Patent 3,076,802 20-[w-(TERTIARY-AMINO)LOWER ALKANOYLAMI- D] PREGN-S-EN-Zifl-OLS, ESTERS CORRESPOND- ING, AND INTERMEDIATES THERETO Raymond E. Counsel], Skokie, Ill., assignor to G. D. Searle & Co., Chi. ago, Ill., a corporation of Delaware No Drawing. Filed Dec. 1, 1961, Ser. No. 156,475 11 Claims. (Cl. 260239.5)

The present invention is concerned with novel steroidal amino-amides of the pregnane series and, more particularly, with 20-[w-(tertiary-amino)lower alkanoylamido] pregn--en-3B-ols and esters thereof, which are represented by the structural formula CHM/v NHCOAlk-Z CH3 wherein R is hydrogen or a lower alkanoyl radical, Alk is a lower alkylene radical, Z is the residue of a secondary amine selected from the group consisting of di-(lower alky1)amines, cycloalkylamines, morpholine, and N-alkylpiperazines, and the wavy line indicates the alternative or or p configuration of the substituent at carbon atom 20 succinate, phosphate, sulfate, hydrobromide, and hydrochloride.

Starting materials suitable for the manufacture of the instant compounds are the 20-aminopregn-S-en-Bfl-ols and corresponding B-esters. The ZO-aminopregn-S-en-SB-ol 3-esters are allowed to react with a chloroalkanoyl chloride to afford the corresponding chloroalkanoylamido compounds. Treatment of these novel intermediates with the appropriate secondary amine results in the tertiaryamino) alkanoylamido 3-esters of this invention. These processes are specifically illustrated by the acylationof ZOa-arninOpregn-S-en-3;3-ol B-acetate with chloroacetyl chloride to yield the novel 20a-chloroacetamidopregn-S- en-3B-ol 3-acetate, which is treated with dimethylamine to produce 20a-(dimethylaminoacetamido)pregn-5-en-3B-ol 3-acetate. When the 20 aminopregn-S-en-3B-ols are utilized as starting materials, two molecular equivalents of the chloroalkanoyl chloride are required, resulting in acylation of the B-hydroxy group also. Treatment of these ester-amides with aqueous potassium hydroxide in dioxane results in preferential hydrolysis of the ester group to yield the chloroalkanoylamido substances, which are treated with a secondary amine, resutling in the instant (tertiary-amino)alkanoylamido-S-ols. The reaction of 20fi-aminopregn-5-en-3[3-01, for example, with 2 molecular equivalents of chloroacetyl chloride affords the novel intermediate, 20,8-(chloroacetamido)-pregn-5-en-3/3-ol 3- chloroacetate, which yields ZOB-(chloroacetamido)pregn- S-en-BB-ol upon hydrolysis with aqueous potassium hy- 3,076,802 Patented Feb. 5, 1963' droxide and dioxane. This chloroamide is allowed to react with dimethylamine in butanone to produce ZOfl-(dimethylaminoacetamido)pregn-S-en-Sfi-ol.

The instant 3 3-hydroxy compounds can, alternatively, be obtained by hydrolysis of the corresponding 3-esters. Typically, 20oz-(dimethylaminoacetamido)pregn-S-en-Iiflol B-acetate is allowed to react with aqueous potassium hydroxide in dioxane to yield the free 313-01.

The 3 8-(lower alkanoates) of this invention can be manufactured also by acylation of the corresponding 3,6- ols, suitably by reaction with a lower alkanoic acid anhydride in pyridine. 20cc (dimethylaminoacetamido) pregn-S-en-sfl-ol, for example, is treated with propionic anhydride and pyridine to afford the corresponding 3- propionate.

The compounds of this invention display valuable pharmacological properties. They are, for example, hypochlolesterolemic agents as is evidenced by their ability to inhibit the hepatic synthesis of cholesterol. They are also antibiotic agents in view of their ability to inhibit the growth of Chlorella vulgaris. In addition, these com- Example 1 To a solution of 18 parts of 20ot-aminopregn-5-en-3flol 3-acetate in 240 parts of benzene containing 7.3 parts of triethylamine is added dropwise a solution of 7.5 parts of chloroacetyl chloride in 20 parts of benzene, and this mixture is stirred and heated at reflux for about one hour, then cooled and filtered. The filter cake is washed with benzene, and the filtrate is washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate, and water, dried over anhydrous sodium sulfate containing decolorizing carbon, and stripped of solvent at reduced pressure. The residue is crystallized from ethanol to yield 20w(chloroacetamido)pregn-5-en-3B-ol S-acetate, Ml. about 196-199"; [a] =--44. This compound is represented by the structural formula n-o-mnoocmol CHI me i Example 2 CHsCO0-- The substitution of 15.9 parts of ZOB-arninopregn-S-en- 35-01 and 16.9 parts of fl-chloropropionyl chloride in the process of Example 1 results in ZOB-(B-chloropropionyl- -amido) -pregn-5-en-3/3-o1 3- fi-chloropropionate) Example 3 Amounts of materials are given in en-Bfi-ol 3-chloroacetate, which is presented by the structural formula I CHa-(5NHC 011101 CH3 H30 I ClCHaCOO- Example 4 Example 5 To a solution of 8.72 parts of 20a-(chloroacetamidojpregn-5 en-3fl-ol 3-acetate in 87 parts of toluene containing 20 parts of butanone is added-a solution of 9 parts of dimethylamine in 26 parts of toluene, and this mixture is heated at 50-55 in a. suitable sealed container for about 40 hours. The reaction mixture is cooled, washed with water, dried. over anhydrous potassium carbonate containing. decolorizing carbon, and evaporated to dryness at reduced pressure. The resulting residueis crystallized from heptane to produce 20a-(dimethylaminoacetamido)pregn-5-en-3fi-ol. 3-acetate, M.P. about 159-161.5;

[a] =52.5. This substance is represented by the structural formula 9 I HCNHOOCH:N(CH:)':

Example 6 The substitution of 43.2 parts of ZOa-(dimethylaminoacetamido)pregn-5-en-3fl-ol 3-acetate in the procedure of Example 4 results in 20a-(dimethylaminoacetamido)- pregn-5-en-3 3-ol, M.P. about 188-189, which is represented by the structural formula Example 7 A solution of 4.4 parts of 20w(chloroacetamido)preg 5 en-3B-ol S-acetate and 1.7 parts ;of p-yrrolidinein 44 parts of benzene is heated at reflux for about 20 hours, then is allowed to cool to room temperature and is diluted with ether. The organic mixture is washed with water, dried over anhydrous potassium carbonate containing decolorizing carbon, and evaporated to dryness in vacuo. The resulting crystalline residue is recrystallized from aqueous ethanol to yield pure 20a-(pyrrolidinoacetamido)pregn-5-en-3;8-ol 3-acetate, M.P. about 157-160", which is represented by the structural formula CHaCOO Example 8 By substituting 2.08 parts of morpholine and otherwise proceeding according to the processes of Example 7, 20a- (morpholinoacetamido)pregn-S-en-Zifl ol 3-acetate, M.P. about 173176, is obtained. This compound is represented by the structural formula l n-o-NnooornN 0 on, E30

Example 9 The substitution of 2.39 parts of N-methylpiperazine in the procedure of Example 7 results in 20a[(N-methylpiperazino)acetamido]pregn-5-en-3B-ol B-acetate, M.P. about -147. It is represented by the structural formula N-CH) Example 10 The substitution of 2.04 parts of piperidine in'the'proced'ure of Example 7 produces a'material, which is recrystallized from methanol to aflord 20a-(piperidinoacetamido)pregn-5-en-3fl-ol 3-acetate, M.P. about 171.5- 172.5. It is represented by the structural formula Example 11 A solution of 9 parts of 20a-(chloroa'cetamido)-pregn- 5;en-3B ol 3-acetate and 4.4 parts of'diethylamine inl54- parts of benzene is heated at 5055 in a suitable sealed container for about 48 hours. The cooled mixture is filtered, and the filtrate is evaporated to dryness in vacuo. Crystallization of the solid residue from aqueous methanol afiords 20a-(diethylaminoacetamido)pregn-S-en-BB- ol S-acetate, M.P. about 147149, which is represented by the structural formula CBS 11 GHaCOO Example 12 The reaction of 8.1 parts of 20fi-(,B-chloropropionamido)pregn--en-3,6-ol with 14.6 parts of diethylamine according to the procedure of Example 5 results in 20/?- (B-diethylaminopropionamido)pregn-S-enfifi-ol, which is represented by the structural formula Example 13 A mixture of one part of 20 8-(fi-diethylarninopropionamido)pregn-5-en-3Bol, 13 parts of propionic anhydride, and 20 parts of pyridine is kept at room temperature for about 16 hours, then is diluted with ice and water. The resulting aqueous mixture is made alkaline to pH 9 by the addition of sodium carbonate, then is extracted with benzene. This organic solution is washed with water,

, N dried over anhydrous sodium sulfate, and concentrated to ryness to produce 201%(,B-diethylaminopropionamido) pregn-S-en-SSB-ol 3-propionate. This compound is represented by the structural formula CHaCHaCOO- Example 14 By substituting one part of ZOa-(dimethyIaminoacetamido)pregn-5-en-3p-ol in the procedure of Example 13, 20w(dimethylaminoacetamido)pregn-S-en-Bfl-ol 3-propionate is obtained. This compound is represented by thestructural formula CHsCHrCOQ- What is claimed is: 1. A compound of the structural formula wherein R is selected from the group consisting of hydrogen and lower alkanoyl radicals, Alk is a lower alkylene radical, and Z is selected from the group consisting of di- (lower alkyl)arnino radicals and radicals of the structural formula N (XL,

wherein X is selected from the group consisting of methylene, epoxy, and methylimino radicals, and n is selected from the group consisting of 0 and l.

2. A compound of the structural formula CH NHC O Alli-Z CH 

1. A COMPOUND OF THE STRUCTURAL FORMULA 